11-78079609-G-T

Variant names:

• chr11-78079609-G-T
• rs8875
• NM_004549.6:c.136C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_004549.6(NDUFC2):​c.136C>A​(p.Leu46Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NDUFC2 NM_004549.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0690
• Publications: 29 publications found

Genes affected

NDUFC2 (HGNC:7706): (NADH:ubiquinone oxidoreductase subunit C2) Involved in mitochondrial respiratory chain complex I assembly. Located in mitochondrion. Part of mitochondrial respiratory chain complex I. Implicated in nuclear type mitochondrial complex I deficiency. [provided by Alliance of Genome Resources, Apr 2022]

NDUFC2-KCTD14 (HGNC:42956): (NDUFC2-KCTD14 readthrough) This locus represents naturally occurring read-through transcription between the neighboring NDUFC2 (NADH dehydrogenase (ubiquinone) 1, subcomplex unknown, 2, 14.5kDa) and KCTD14 (potassium channel tetramerisation domain containing 14) genes on chromosome 11. The read-through transcripts share sequence identity with the upstream gene product and one variant has a frameshifted C-terminal region derived from the downstream gene exons. [provided by RefSeq, Feb 2011]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 0.23764 (below the threshold of 3.09). Trascript score misZ: -0.065329 (below the threshold of 3.09). GenCC associations: The gene is linked to mitochondrial disease, Leigh syndrome, mitochondrial complex I deficiency, nuclear type 36.
• BP4: Computational evidence support a benign effect (MetaRNN=0.079265594).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004549.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFC2	NM_004549.6	MANE Select	c.136C>A	p.Leu46Ile	missense	Exon 1 of 3	NP_004540.1
	NDUFC2-KCTD14	NM_001203260.2		c.136C>A	p.Leu46Ile	missense	Exon 1 of 4	NP_001190189.1
	NDUFC2-KCTD14	NM_001203261.2		c.136C>A	p.Leu46Ile	missense	Exon 1 of 3	NP_001190190.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFC2	ENST00000281031.5	TSL:1 MANE Select	c.136C>A	p.Leu46Ile	missense	Exon 1 of 3	ENSP00000281031.4
	NDUFC2-KCTD14	ENST00000530054.1	TSL:2	c.136C>A	p.Leu46Ile	missense	Exon 1 of 3	ENSP00000432614.1
	NDUFC2-KCTD14	ENST00000612612.5	TSL:2	c.136C>A	p.Leu46Ile	missense	Exon 1 of 4	ENSP00000478766.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00 AC: 0 AN: 167340 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1409690 Hom.: 0 Cov.: 66 AF XY: 0.00 AC XY: 0 AN XY: 696450

African (AFR) AF: 0.00 AC: 0 AN: 32192

American (AMR) AF: 0.00 AC: 0 AN: 36778

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25254

East Asian (EAS) AF: 0.00 AC: 0 AN: 36830

South Asian (SAS) AF: 0.00 AC: 0 AN: 80210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49838

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4684

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1085604

Other (OTH) AF: 0.00 AC: 0 AN: 58300

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	11
DANN	Benign	0.57
DEOGEN2	Benign	0.016	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0052	N
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.079	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L
PhyloP100		0.069
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.029
Sift	Benign	0.34	T
Sift4G	Benign	0.43	T
Polyphen		0.10	B
Vest4		0.15
MutPred		0.25		Loss of catalytic residue at L46 (P = 0.0599)
MVP		0.085
MPC		0.68
ClinPred		0.080	T
GERP RS		-0.89
PromoterAI		-0.012	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.092
gMVP		0.28
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs8875; hg19: chr11-77790655;